Comments

The Takashima mice are remarkable, as they appear to express high levels of
the mutant tau protein in only a very few cells in the brain: that is, in
some of the pyramidal cells of the hippocampus. Apparently the transgene is expressed at only very low levels in the rest of the brain, although it is possible that there are other cell groups that also show high expression. In the pyramidal cells, it appears that
high-level expression of the mutant tau protein leads to hyperphosphorylation, some aggregation (although it is unclear exactly how much aggregation there is), and cell dysfunction. Because of the very limited number of cells expressing the mutant protein, it appears that the mice will survive (unlike the Lewis/Hutton mice) to advanced age. The authors state that up to 70 percent of the tau in the hippocampus is the mutant protein, and this would suggest that the level of mutant human tau in the pyramidal cells is several fold above normal. This may also be why the cells are sick. High levels of a mutant tau protein are probably bad for cells. It is unclear what relevance these mice may have for studies of
Alzheimer's disease, but it is an interesting model of tau-mediated cell dysfunction in the hippocampus.

In related news, the Mandelkow's paper continues their fine work trying to
unravel the mechanism of PHF formation by in vitro studies of structural changes that occur in tau on aggregation. Their identification of regions of tau that seem to be important for aggregation through beta-sheet formation is probably relevant to the mechanism of PHF formation in AD. They are the only group (to my knowledge) to be able to show formation of true paired helical filament structures using mutant tau constructs. Although this is a rather esoteric point, there is some debate about whether neuronal death in the tau mutation cases involves PHF formation as a necessary step. In one of the mutations they use in their study, P301L, the human disease does not appear to involve extensive PHF formation. The
Mandelkows discuss the possible mechanisms of cell death in tau mutation cases at some length, and it is clear that in most cases, more than one mechanism might participate in killing cells. However, these mechanistic studies point to important hypotheses that can be tested in cellular and perhaps animal models. For example, it will be very interesting to see if
transgenic mice with the deletion of lysine at position 280 would show early and extensive PHF formation, as this in vitro work clearly suggests. No doubt attempts to make these mice are already underway.

Reply by Akihiko Takashima
Regarding Peter Davies' comment, I would like to reply. We observed human tau expression in the entire brain where the PDGF promoter activates. In the hippocampus region, exogenously expressing human tau is highly accumulated in neurons, and some neurons exhibited positive staining for histological markers for NFTs. This may be not due to higher expression of human tau specifically in hippocampus of Tg mice, but to the reduction of tau degradation. Human tau mRNA expression was almost the same level as endogenous mouse tau, despite the fact that human tau protein level was only 10 percent of endogenous tau in other brain areas. Now we don't know what mechanism is involved in the degradation of exogenous tau, and why the degradation of tau is inhibited in hippocampal neurons of aged Tg mice. Because NFTs frequently occur in the hippocampus of aging and AD brain, I think that these are important points to resolve the mechanism of neurodegeneration through tau accumulation in AD.

Regarding the relevance of FTDP-17 Tg mice to the study of AD: as we know, Aβ accumulation may be a cause of AD. AβPP Tg mice with FAD mutation showed Aβ deposition and behavioral change but no neuronal loss or NFTs. Recently, the crossbreeds of tau Tg with AβPP Tg mice resulted in accelerated NFT formation, and Aβ injection into hippocampus of tau Tg mice showed the formation of NFTs in amygdala (Lewis et al, 2001; Gotz et al. 2001; see related news item). It is possible to interpret these results such that Aβ can accelerate NFT formation when tau is accumulated in the cytoplasm of neurons.

In normal aging, neurons in the entorhinal cortex and hippocampus can form NFTs without forming Aβ deposition by age 75, suggesting that the process of brain aging activates the formation of NFTs via an Aβ-independent mechanism. If FTD-17 mutations of tau are an accelerating factor for the process of brain aging, and brain aging in mutant tau Tg mice is progressing faster compared to normal mice, then Aβ deposition further accelerates the brain aging and formation of NFTs.